US20060160827A1 - Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith - Google Patents
Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith Download PDFInfo
- Publication number
- US20060160827A1 US20060160827A1 US11/364,425 US36442506A US2006160827A1 US 20060160827 A1 US20060160827 A1 US 20060160827A1 US 36442506 A US36442506 A US 36442506A US 2006160827 A1 US2006160827 A1 US 2006160827A1
- Authority
- US
- United States
- Prior art keywords
- compounds
- indolo
- dione
- quinazoline
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- HJEDFLMBDMLNPF-UHFFFAOYSA-N CC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 Chemical compound CC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 HJEDFLMBDMLNPF-UHFFFAOYSA-N 0.000 description 3
- KEHDGBIHPULQBU-UHFFFAOYSA-N O=C1C2=CC(OC(F)(F)F)=CC=C2N2C(=O)C3=C(C=C(F)C=C3)N=C12 Chemical compound O=C1C2=CC(OC(F)(F)F)=CC=C2N2C(=O)C3=C(C=C(F)C=C3)N=C12 KEHDGBIHPULQBU-UHFFFAOYSA-N 0.000 description 3
- 0 [1*]*1=C2C(=O)N3C(=NC2=[2H]([4*])C([3*])=B1[2*])C(=C)C1=C([5*])F([6*])=C([7*])[H]([8*])=C13 Chemical compound [1*]*1=C2C(=O)N3C(=NC2=[2H]([4*])C([3*])=B1[2*])C(=C)C1=C([5*])F([6*])=C([7*])[H]([8*])=C13 0.000 description 3
- WGQNOVHKRYKTET-UHFFFAOYSA-N CC1=CC2=C(N=C3C(=O)C4=CC(F)=CC=C4N3C2=O)C(C)=C1 Chemical compound CC1=CC2=C(N=C3C(=O)C4=CC(F)=CC=C4N3C2=O)C(C)=C1 WGQNOVHKRYKTET-UHFFFAOYSA-N 0.000 description 2
- XNTNBPWHNOEVIE-UHFFFAOYSA-N CC1=NC2=C(C=N1)C(=O)N1C3=CC=CC=C3C(=O)C1=N2 Chemical compound CC1=NC2=C(C=N1)C(=O)N1C3=CC=CC=C3C(=O)C1=N2 XNTNBPWHNOEVIE-UHFFFAOYSA-N 0.000 description 2
- HXWNYCKVLMZCIL-UHFFFAOYSA-N CC1CN(C2=CC3=C(C=C2F)C(=O)N2C4=CC=C(I)C=C4C(=O)C2=N3)CCN1.O=C(O)C(F)(F)F Chemical compound CC1CN(C2=CC3=C(C=C2F)C(=O)N2C4=CC=C(I)C=C4C(=O)C2=N3)CCN1.O=C(O)C(F)(F)F HXWNYCKVLMZCIL-UHFFFAOYSA-N 0.000 description 2
- GGSWNOUXXLANOG-UHFFFAOYSA-N CCOC(=O)C1=NC2=C(C=CC=C2)C(=O)N1C1=CC=CC=C1 Chemical compound CCOC(=O)C1=NC2=C(C=CC=C2)C(=O)N1C1=CC=CC=C1 GGSWNOUXXLANOG-UHFFFAOYSA-N 0.000 description 2
- DGCWSSLVLNPSLK-UHFFFAOYSA-N O=C1C2=CC(Br)=CC=C2N2C(=O)C3=C(C=NC=C3)N=C12 Chemical compound O=C1C2=CC(Br)=CC=C2N2C(=O)C3=C(C=NC=C3)N=C12 DGCWSSLVLNPSLK-UHFFFAOYSA-N 0.000 description 2
- SEZNGBCXCAHAEW-UHFFFAOYSA-N O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(C=C(F)C=C3)N=C12 Chemical compound O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(C=C(F)C=C3)N=C12 SEZNGBCXCAHAEW-UHFFFAOYSA-N 0.000 description 2
- AKHMUNBSKUODAD-UHFFFAOYSA-N O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(N=CC=C3)N=C12 Chemical compound O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(N=CC=C3)N=C12 AKHMUNBSKUODAD-UHFFFAOYSA-N 0.000 description 2
- UQEXDUSAMXWQHW-UHFFFAOYSA-N C=C(CCCCCC)OOCCN(C)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 Chemical compound C=C(CCCCCC)OOCCN(C)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 UQEXDUSAMXWQHW-UHFFFAOYSA-N 0.000 description 1
- WUJFPBDZECGVBQ-JWGURIENSA-N CC(C)(C)OC(=O)N/N=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound CC(C)(C)OC(=O)N/N=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 WUJFPBDZECGVBQ-JWGURIENSA-N 0.000 description 1
- MIKKQLUXOXIUCY-UHFFFAOYSA-N CC1(C)COC(C2=CC=C3C(=C2)C(=O)C2=NC4=CC=NC=C4C(=O)N32)OC1 Chemical compound CC1(C)COC(C2=CC=C3C(=C2)C(=O)C2=NC4=CC=NC=C4C(=O)N32)OC1 MIKKQLUXOXIUCY-UHFFFAOYSA-N 0.000 description 1
- WAZOTTKNAAAVBP-UHFFFAOYSA-N CC1=CC2=C(C=C1)N=C1C(=O)C3=CC(F)=CC=C3N1C2=O Chemical compound CC1=CC2=C(C=C1)N=C1C(=O)C3=CC(F)=CC=C3N1C2=O WAZOTTKNAAAVBP-UHFFFAOYSA-N 0.000 description 1
- WCVZUFADLNRHLS-UHFFFAOYSA-N CC1=CC2=C(C=C1)N=C1C(=O)C3=CC=CC=C3N1C2=O Chemical compound CC1=CC2=C(C=C1)N=C1C(=O)C3=CC=CC=C3N1C2=O WCVZUFADLNRHLS-UHFFFAOYSA-N 0.000 description 1
- WKERHFATHGQILN-GFMRDNFCSA-N CC1=CC=C(S(=O)(=O)N/N=C2/C3=CC=CC=C3N3C(=O)C4=C(C=CC=C4)N=C23)C=C1 Chemical compound CC1=CC=C(S(=O)(=O)N/N=C2/C3=CC=CC=C3N3C(=O)C4=C(C=CC=C4)N=C23)C=C1 WKERHFATHGQILN-GFMRDNFCSA-N 0.000 description 1
- BLKZWDXMVLWQNU-UHFFFAOYSA-N CC1=CC=CC2=C1C(=O)N1C3=CC=C(F)C=C3C(=O)C1=N2 Chemical compound CC1=CC=CC2=C1C(=O)N1C3=CC=C(F)C=C3C(=O)C1=N2 BLKZWDXMVLWQNU-UHFFFAOYSA-N 0.000 description 1
- XKPQOJHOZJZGTE-UHFFFAOYSA-N CC1=CC=CC2=C1N=C1C(=O)C3=CC(F)=CC=C3N1C2=O Chemical compound CC1=CC=CC2=C1N=C1C(=O)C3=CC(F)=CC=C3N1C2=O XKPQOJHOZJZGTE-UHFFFAOYSA-N 0.000 description 1
- GWNRKHUJGUTCJU-UHFFFAOYSA-N CC1=CC=CC2=C1N=C1C(=O)C3=CC=CC=C3N1C2=O Chemical compound CC1=CC=CC2=C1N=C1C(=O)C3=CC=CC=C3N1C2=O GWNRKHUJGUTCJU-UHFFFAOYSA-N 0.000 description 1
- LUKVBMLPWLVNLZ-UHFFFAOYSA-N CC1=NC2=C(C=N1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 Chemical compound CC1=NC2=C(C=N1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 LUKVBMLPWLVNLZ-UHFFFAOYSA-N 0.000 description 1
- MIUGDPBHLBHVIO-UHFFFAOYSA-N CC1=NC2=C(C=N1)C(=O)N1C3=CC=C(I)C=C3C(=O)C1=N2 Chemical compound CC1=NC2=C(C=N1)C(=O)N1C3=CC=C(I)C=C3C(=O)C1=N2 MIUGDPBHLBHVIO-UHFFFAOYSA-N 0.000 description 1
- QHMACISKUZSRDT-UHFFFAOYSA-N CCC1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 Chemical compound CCC1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 QHMACISKUZSRDT-UHFFFAOYSA-N 0.000 description 1
- MWVLTABHKRFJTM-UHFFFAOYSA-N CCCCCCC(C)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 Chemical compound CCCCCCC(C)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 MWVLTABHKRFJTM-UHFFFAOYSA-N 0.000 description 1
- UMFBXNDIKFNRNG-UHFFFAOYSA-N CCCCCCCCC1=CC2=C(C=C1)N=C1C(=O)C3=CC(Cl)=CC=C3N1C2=O Chemical compound CCCCCCCCC1=CC2=C(C=C1)N=C1C(=O)C3=CC(Cl)=CC=C3N1C2=O UMFBXNDIKFNRNG-UHFFFAOYSA-N 0.000 description 1
- IMIXNNFLXRWSSN-UHFFFAOYSA-N CCCCCCCCC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=CC(N(C)CCO)=C3)C(=O)N21 Chemical compound CCCCCCCCC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=CC(N(C)CCO)=C3)C(=O)N21 IMIXNNFLXRWSSN-UHFFFAOYSA-N 0.000 description 1
- UPUHAJIQCIVFBJ-UHFFFAOYSA-N CCCCCCCCC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 Chemical compound CCCCCCCCC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 UPUHAJIQCIVFBJ-UHFFFAOYSA-N 0.000 description 1
- WMPPXDOYXHOQEF-UHFFFAOYSA-N CCN(CCN(C)C)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 Chemical compound CCN(CCN(C)C)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 WMPPXDOYXHOQEF-UHFFFAOYSA-N 0.000 description 1
- UURSREIBFJDEOI-UHFFFAOYSA-N CCOC(=O)C(O)(C(=O)OCC)C1C2=CC(F)=CC=C2N2C(=O)C3=C(N=C12)C(OC)=CC=C3 Chemical compound CCOC(=O)C(O)(C(=O)OCC)C1C2=CC(F)=CC=C2N2C(=O)C3=C(N=C12)C(OC)=CC=C3 UURSREIBFJDEOI-UHFFFAOYSA-N 0.000 description 1
- HLUWIFUMLFCUFQ-UHFFFAOYSA-N CCOC(=O)C(O)(C(=O)OCC)C1C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound CCOC(=O)C(O)(C(=O)OCC)C1C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 HLUWIFUMLFCUFQ-UHFFFAOYSA-N 0.000 description 1
- QRCKKUIEOHLLMU-UHFFFAOYSA-N CCOC(=O)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=C(I)C=C3)C(=O)N21 Chemical compound CCOC(=O)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=C(I)C=C3)C(=O)N21 QRCKKUIEOHLLMU-UHFFFAOYSA-N 0.000 description 1
- LEQQOARDEVZVCM-UHFFFAOYSA-N CCOC(=O)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=CC=N3)C(=O)N21 Chemical compound CCOC(=O)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=CC=N3)C(=O)N21 LEQQOARDEVZVCM-UHFFFAOYSA-N 0.000 description 1
- NGSBCNPKNUBBOE-UHFFFAOYSA-N CFF.O=C1C2=CC(C(O)(F)C(F)(F)F)=CC=C2N2C(=O)C3=CN=CC=C3N=C12 Chemical compound CFF.O=C1C2=CC(C(O)(F)C(F)(F)F)=CC=C2N2C(=O)C3=CN=CC=C3N=C12 NGSBCNPKNUBBOE-UHFFFAOYSA-N 0.000 description 1
- RUAKBJBFRSVJDB-LVZFUZTISA-N CN(C)CC/N=C1\C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound CN(C)CC/N=C1\C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 RUAKBJBFRSVJDB-LVZFUZTISA-N 0.000 description 1
- RENUJJCCRLJECC-UHFFFAOYSA-N CN(CC(=O)O)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 Chemical compound CN(CC(=O)O)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 RENUJJCCRLJECC-UHFFFAOYSA-N 0.000 description 1
- VXQAWJFWUHLEFX-UHFFFAOYSA-N CN(CCO)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 Chemical compound CN(CCO)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 VXQAWJFWUHLEFX-UHFFFAOYSA-N 0.000 description 1
- XPUYKHZRLSYDNX-UHFFFAOYSA-N CN(CCO)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(F)C=C3C(=O)C1=N2 Chemical compound CN(CCO)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(F)C=C3C(=O)C1=N2 XPUYKHZRLSYDNX-UHFFFAOYSA-N 0.000 description 1
- KLIQASAOKOFSFP-UHFFFAOYSA-N CN(CCO)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(OC(F)(F)F)C=C3C(=O)C1=N2 Chemical compound CN(CCO)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(OC(F)(F)F)C=C3C(=O)C1=N2 KLIQASAOKOFSFP-UHFFFAOYSA-N 0.000 description 1
- WIFHHQXJLZSVRG-UHFFFAOYSA-N CN(CCOC(=O)CCC(=O)O)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 Chemical compound CN(CCOC(=O)CCC(=O)O)C1=CC2=C(C=C1)C(=O)N1C3=CC=C(Cl)C=C3C(=O)C1=N2 WIFHHQXJLZSVRG-UHFFFAOYSA-N 0.000 description 1
- MGEJSFXFRHQTDT-JJFYIABZSA-N CN1CCN(/N=C\C2=CC=C3C(=C2)C(=O)C2=NC4=C(C=NC=C4)C(=O)N32)CC1 Chemical compound CN1CCN(/N=C\C2=CC=C3C(=C2)C(=O)C2=NC4=C(C=NC=C4)C(=O)N32)CC1 MGEJSFXFRHQTDT-JJFYIABZSA-N 0.000 description 1
- VSJDFIRDABCLIB-UHFFFAOYSA-N CN1CCN(C2=C(F)C=C3C(=O)C4=NC5=C(C=CC(F)=C5)C(=O)N4C3=C2)CC1 Chemical compound CN1CCN(C2=C(F)C=C3C(=O)C4=NC5=C(C=CC(F)=C5)C(=O)N4C3=C2)CC1 VSJDFIRDABCLIB-UHFFFAOYSA-N 0.000 description 1
- FLCMFXCWRKPSTM-UHFFFAOYSA-N CN1CCN(C2=C(F)C=C3C(=O)C4=NC5=C(C=CC=C5)C(=O)N4C3=C2)CC1 Chemical compound CN1CCN(C2=C(F)C=C3C(=O)C4=NC5=C(C=CC=C5)C(=O)N4C3=C2)CC1 FLCMFXCWRKPSTM-UHFFFAOYSA-N 0.000 description 1
- OLQLYQJEEXNPRX-UHFFFAOYSA-N CN1CCN(C2=CC3=C(C=C2)C(=O)N2C4=CC=C(Cl)C=C4C(=O)C2=N3)CC1 Chemical compound CN1CCN(C2=CC3=C(C=C2)C(=O)N2C4=CC=C(Cl)C=C4C(=O)C2=N3)CC1 OLQLYQJEEXNPRX-UHFFFAOYSA-N 0.000 description 1
- STCYUIIPFUFSGA-UHFFFAOYSA-N CN1CCN(C2=CC3=C(C=C2)C(=O)N2C4=CC=C(F)C=C4C(=O)C2=N3)CC1 Chemical compound CN1CCN(C2=CC3=C(C=C2)C(=O)N2C4=CC=C(F)C=C4C(=O)C2=N3)CC1 STCYUIIPFUFSGA-UHFFFAOYSA-N 0.000 description 1
- WRVHQKVQLUQKGD-UHFFFAOYSA-N CN1CCN(C2=CC=C3C(=O)C4=NC5=C(C=CC=C5)C(=O)N4C3=C2)CC1 Chemical compound CN1CCN(C2=CC=C3C(=O)C4=NC5=C(C=CC=C5)C(=O)N4C3=C2)CC1 WRVHQKVQLUQKGD-UHFFFAOYSA-N 0.000 description 1
- SIENDNZAXMIHAI-UHFFFAOYSA-N COC(=O)N1CCN(C2=CC3=C(C=C2F)C(=O)N2C4=CC=C(I)C=C4C(=O)C2=N3)CC1 Chemical compound COC(=O)N1CCN(C2=CC3=C(C=C2F)C(=O)N2C4=CC=C(I)C=C4C(=O)C2=N3)CC1 SIENDNZAXMIHAI-UHFFFAOYSA-N 0.000 description 1
- HGXNBRRIBIJESI-UHFFFAOYSA-N COC(C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21)C(C)C Chemical compound COC(C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21)C(C)C HGXNBRRIBIJESI-UHFFFAOYSA-N 0.000 description 1
- SHAXCACKKVACQN-UHFFFAOYSA-N COC(OC)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 Chemical compound COC(OC)C1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 SHAXCACKKVACQN-UHFFFAOYSA-N 0.000 description 1
- JWOZXZYZCJZGRQ-LDADJPATSA-N COC1=CC=CC2=C1N=C1/C(=C/C3=CC=CC=C3)C3=CC(F)=CC=C3N1C2=O Chemical compound COC1=CC=CC2=C1N=C1/C(=C/C3=CC=CC=C3)C3=CC(F)=CC=C3N1C2=O JWOZXZYZCJZGRQ-LDADJPATSA-N 0.000 description 1
- BODHONFKPSQHDK-UHFFFAOYSA-N COC1=CC=CC2=C1N=C1C(=O)C3=CC(I)=CC=C3N1C2=O Chemical compound COC1=CC=CC2=C1N=C1C(=O)C3=CC(I)=CC=C3N1C2=O BODHONFKPSQHDK-UHFFFAOYSA-N 0.000 description 1
- URNXJGOSAPMLHH-UHFFFAOYSA-N COC1=CC=CC2=C1N=C1C(=O)C3=CC=CC=C3N1C2=O Chemical compound COC1=CC=CC2=C1N=C1C(=O)C3=CC=CC=C3N1C2=O URNXJGOSAPMLHH-UHFFFAOYSA-N 0.000 description 1
- WGWZQOPHRJPUTP-UHFFFAOYSA-N COCC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 Chemical compound COCC1=CC=C2C(=C1)C(=O)C1=NC3=C(C=NC=C3)C(=O)N21 WGWZQOPHRJPUTP-UHFFFAOYSA-N 0.000 description 1
- MNZNHGZNWJPGDJ-UHFFFAOYSA-N COCCOC(C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21)C(C)C Chemical compound COCCOC(C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21)C(C)C MNZNHGZNWJPGDJ-UHFFFAOYSA-N 0.000 description 1
- IHLJCISMOZGHMK-UYRXBGFRSA-N NC(=O)N/N=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound NC(=O)N/N=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 IHLJCISMOZGHMK-UYRXBGFRSA-N 0.000 description 1
- WCBYBJRMPHYAEY-UHFFFAOYSA-N NC1=CC2=C(C=C1)N=C1C(=O)C3=CC(F)=CC=C3N1C2=O Chemical compound NC1=CC2=C(C=C1)N=C1C(=O)C3=CC(F)=CC=C3N1C2=O WCBYBJRMPHYAEY-UHFFFAOYSA-N 0.000 description 1
- SUJWNODHBNTEOF-HKOYGPOVSA-N O=C(N/N=C1\C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12)C1=CC=NC=C1 Chemical compound O=C(N/N=C1\C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12)C1=CC=NC=C1 SUJWNODHBNTEOF-HKOYGPOVSA-N 0.000 description 1
- ZIYQQACQCVLYOG-UHFFFAOYSA-N O=C(O)CCC1COC2(N1)C1=CC=CC=C1N1C(=O)C3=C(C=CC=C3)N=C12 Chemical compound O=C(O)CCC1COC2(N1)C1=CC=CC=C1N1C(=O)C3=C(C=CC=C3)N=C12 ZIYQQACQCVLYOG-UHFFFAOYSA-N 0.000 description 1
- DXENDDMPDZMHSQ-VXPUYCOJSA-N O=C1C2=C(C=CC=C2)N/C1=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound O=C1C2=C(C=CC=C2)N/C1=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 DXENDDMPDZMHSQ-VXPUYCOJSA-N 0.000 description 1
- PIRIEFMISCVFIL-SFRRXYARSA-N O=C1C2=C(C=CC=C2)N=C2/C(=C/C=C/C3=CC=CC=C3)C3=CC=CC=C3N12 Chemical compound O=C1C2=C(C=CC=C2)N=C2/C(=C/C=C/C3=CC=CC=C3)C3=CC=CC=C3N12 PIRIEFMISCVFIL-SFRRXYARSA-N 0.000 description 1
- HINUIMNQFYZLFK-UHFFFAOYSA-N O=C1C2=C(C=CC=C2)N=C2OC3=CC=CC=C3N12 Chemical compound O=C1C2=C(C=CC=C2)N=C2OC3=CC=CC=C3N12 HINUIMNQFYZLFK-UHFFFAOYSA-N 0.000 description 1
- YSYFIWDTNXUQCF-UHFFFAOYSA-N O=C1C2=C(C=CC=C2)N=C2SC3=CC=CC=C3N12 Chemical compound O=C1C2=C(C=CC=C2)N=C2SC3=CC=CC=C3N12 YSYFIWDTNXUQCF-UHFFFAOYSA-N 0.000 description 1
- MIDDVCJFJSGVQD-UHFFFAOYSA-N O=C1C2=CC(Br)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 Chemical compound O=C1C2=CC(Br)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 MIDDVCJFJSGVQD-UHFFFAOYSA-N 0.000 description 1
- LJOJZTDCRDYZAC-UHFFFAOYSA-N O=C1C2=CC(C3CCCCC3)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 Chemical compound O=C1C2=CC(C3CCCCC3)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 LJOJZTDCRDYZAC-UHFFFAOYSA-N 0.000 description 1
- NYZQPMWIXLNGLZ-UHFFFAOYSA-N O=C1C2=CC(C3OCCCO3)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 Chemical compound O=C1C2=CC(C3OCCCO3)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 NYZQPMWIXLNGLZ-UHFFFAOYSA-N 0.000 description 1
- QUVVHRRCMVEHJM-UHFFFAOYSA-N O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=C(F)C=C3)N=C12 Chemical compound O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=C(F)C=C3)N=C12 QUVVHRRCMVEHJM-UHFFFAOYSA-N 0.000 description 1
- CNDYJFSVKNDQAU-UHFFFAOYSA-N O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=C(N4CCCCC4)C=C3)N=C12 Chemical compound O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=C(N4CCCCC4)C=C3)N=C12 CNDYJFSVKNDQAU-UHFFFAOYSA-N 0.000 description 1
- ULNVVWXOXFRMGF-UHFFFAOYSA-N O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=C(SCCO)C=C3)N=C12 Chemical compound O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=C(SCCO)C=C3)N=C12 ULNVVWXOXFRMGF-UHFFFAOYSA-N 0.000 description 1
- UFMIXRQHKLYMBI-UHFFFAOYSA-N O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=CC(I)=C3)N=C12 Chemical compound O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(C=CC(I)=C3)N=C12 UFMIXRQHKLYMBI-UHFFFAOYSA-N 0.000 description 1
- RLMFTPUHPDJABP-UHFFFAOYSA-N O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(N=CC=C3)N=C12 Chemical compound O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(N=CC=C3)N=C12 RLMFTPUHPDJABP-UHFFFAOYSA-N 0.000 description 1
- RRQDSBKJWUWXCO-UHFFFAOYSA-N O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(N=CN=C3)N=C12 Chemical compound O=C1C2=CC(Cl)=CC=C2N2C(=O)C3=C(N=CN=C3)N=C12 RRQDSBKJWUWXCO-UHFFFAOYSA-N 0.000 description 1
- NJKYUPQPDMHUOC-UHFFFAOYSA-N O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(C=CC=C3F)N=C12 Chemical compound O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(C=CC=C3F)N=C12 NJKYUPQPDMHUOC-UHFFFAOYSA-N 0.000 description 1
- VNUXOMSIXIUXEM-UHFFFAOYSA-N O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(N=C12)C(F)=CC=C3 Chemical compound O=C1C2=CC(F)=CC=C2N2C(=O)C3=C(N=C12)C(F)=CC=C3 VNUXOMSIXIUXEM-UHFFFAOYSA-N 0.000 description 1
- UXBGZQXHNVNPFT-UHFFFAOYSA-N O=C1C2=CC(F)=CC=C2N2C(=O)C3=CC=CC=C3N=C12 Chemical compound O=C1C2=CC(F)=CC=C2N2C(=O)C3=CC=CC=C3N=C12 UXBGZQXHNVNPFT-UHFFFAOYSA-N 0.000 description 1
- FYMAQWCFXQLFLF-UHFFFAOYSA-N O=C1C2=CC(I)=CC=C2N2C(=O)C3=C(N=C12)C(Br)=CC(Br)=C3 Chemical compound O=C1C2=CC(I)=CC=C2N2C(=O)C3=C(N=C12)C(Br)=CC(Br)=C3 FYMAQWCFXQLFLF-UHFFFAOYSA-N 0.000 description 1
- YSIAZXUXXZFSDU-UHFFFAOYSA-N O=C1C2=CC(I)=CC=C2N2C(=O)C3=C(N=C12)C(O)=NC(O)=N3 Chemical compound O=C1C2=CC(I)=CC=C2N2C(=O)C3=C(N=C12)C(O)=NC(O)=N3 YSIAZXUXXZFSDU-UHFFFAOYSA-N 0.000 description 1
- UWPRQQPOVGSPTK-UHFFFAOYSA-N O=C1C2=CC(I)=CC=C2N2C(=O)C3=C(N=CC=C3)N=C12 Chemical compound O=C1C2=CC(I)=CC=C2N2C(=O)C3=C(N=CC=C3)N=C12 UWPRQQPOVGSPTK-UHFFFAOYSA-N 0.000 description 1
- MHGHHZKKQAJCDD-UHFFFAOYSA-N O=C1C2=CC(OC(F)(F)F)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 Chemical compound O=C1C2=CC(OC(F)(F)F)=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 MHGHHZKKQAJCDD-UHFFFAOYSA-N 0.000 description 1
- BDZWQXIEJDBCPJ-UHFFFAOYSA-N O=C1C2=CC(OC(F)(F)F)=CC=C2N2C(=O)C3=CC=C(SCCO)C=C3N=C12 Chemical compound O=C1C2=CC(OC(F)(F)F)=CC=C2N2C(=O)C3=CC=C(SCCO)C=C3N=C12 BDZWQXIEJDBCPJ-UHFFFAOYSA-N 0.000 description 1
- GGGNHPLMWCMQBW-UHFFFAOYSA-N O=C1C2=CC=C(Cl)C=C2N2C(=O)C3=C(N=CC=C3)N=C12 Chemical compound O=C1C2=CC=C(Cl)C=C2N2C(=O)C3=C(N=CC=C3)N=C12 GGGNHPLMWCMQBW-UHFFFAOYSA-N 0.000 description 1
- CPZULIGVBXZLGC-UHFFFAOYSA-N O=C1C2=CC=CC=C2N2C(=O)C3=C(C=CC(Br)=C3)N=C12 Chemical compound O=C1C2=CC=CC=C2N2C(=O)C3=C(C=CC(Br)=C3)N=C12 CPZULIGVBXZLGC-UHFFFAOYSA-N 0.000 description 1
- VQQVWGVXDIPORV-UHFFFAOYSA-N O=C1C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound O=C1C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 VQQVWGVXDIPORV-UHFFFAOYSA-N 0.000 description 1
- IYBGGDUSDNEXCZ-UHFFFAOYSA-N O=C1C2=CC=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 Chemical compound O=C1C2=CC=CC=C2N2C(=O)C3=C(C=CN=C3)N=C12 IYBGGDUSDNEXCZ-UHFFFAOYSA-N 0.000 description 1
- ZAVSZXRDGPONBL-UHFFFAOYSA-N O=C1C2=CC=CC=C2N2C(=O)C3=C(N=C12)C(Br)=CC(Br)=C3Cl Chemical compound O=C1C2=CC=CC=C2N2C(=O)C3=C(N=C12)C(Br)=CC(Br)=C3Cl ZAVSZXRDGPONBL-UHFFFAOYSA-N 0.000 description 1
- VVGJLMXSMBVUHD-UHFFFAOYSA-N O=C1C2=CC=CC=C2N2C(=O)C3=C(N=C12)C(Br)=CC(Br)=C3F Chemical compound O=C1C2=CC=CC=C2N2C(=O)C3=C(N=C12)C(Br)=CC(Br)=C3F VVGJLMXSMBVUHD-UHFFFAOYSA-N 0.000 description 1
- KWZXKPFBHSSXLT-UHFFFAOYSA-N O=C1C2=CC=CC=C2N2C(=O)C3=C(N=CC=N3)N=C12 Chemical compound O=C1C2=CC=CC=C2N2C(=O)C3=C(N=CC=N3)N=C12 KWZXKPFBHSSXLT-UHFFFAOYSA-N 0.000 description 1
- DBAMKDUUTLDFTD-UHFFFAOYSA-N O=C1C2=CC=CC=C2N=C2N1C1=CC=CC=C1C21OCCO1 Chemical compound O=C1C2=CC=CC=C2N=C2N1C1=CC=CC=C1C21OCCO1 DBAMKDUUTLDFTD-UHFFFAOYSA-N 0.000 description 1
- SXBMVQSPFHEBPB-UHFFFAOYSA-N O=C1C2=NC3=C(C=CC=C3)C(=O)N2C2=CC=CC(Cl)=C12 Chemical compound O=C1C2=NC3=C(C=CC=C3)C(=O)N2C2=CC=CC(Cl)=C12 SXBMVQSPFHEBPB-UHFFFAOYSA-N 0.000 description 1
- PAOQBRNVKVXNQT-PEZBUJJGSA-N [C-]#[N+]/C(C#N)=C1/C2=CC(F)=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound [C-]#[N+]/C(C#N)=C1/C2=CC(F)=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 PAOQBRNVKVXNQT-PEZBUJJGSA-N 0.000 description 1
- YZNSRKUZEMNIQQ-PEZBUJJGSA-N [C-]#[N+]/C(C#N)=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 Chemical compound [C-]#[N+]/C(C#N)=C1/C2=CC=CC=C2N2C(=O)C3=C(C=CC=C3)N=C12 YZNSRKUZEMNIQQ-PEZBUJJGSA-N 0.000 description 1
- HZDNVKJVYCSNLD-VROXFSQNSA-N [H]/C(=N/N([H])C(=O)C1=CC=NC=C1)C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 Chemical compound [H]/C(=N/N([H])C(=O)C1=CC=NC=C1)C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 HZDNVKJVYCSNLD-VROXFSQNSA-N 0.000 description 1
- HWEOBTAPFBGPMC-SSDVNMTOSA-N [H]/C(=N\N1CCCCC1)C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 Chemical compound [H]/C(=N\N1CCCCC1)C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 HWEOBTAPFBGPMC-SSDVNMTOSA-N 0.000 description 1
- SYRKYKICLIXKSC-AWQFTUOYSA-N [H]/C(=N\OCC=C)C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 Chemical compound [H]/C(=N\OCC=C)C1=CC=C2C(=C1)C(=O)C1=NC3=CC=NC=C3C(=O)N21 SYRKYKICLIXKSC-AWQFTUOYSA-N 0.000 description 1
- FCFCWXGEIXEQKJ-UHFFFAOYSA-N [H]N1C2=C(C=CC=C2)C(=O)N2C3=CC=C(F)C=C3C(=O)C12 Chemical compound [H]N1C2=C(C=CC=C2)C(=O)N2C3=CC=C(F)C=C3C(=O)C12 FCFCWXGEIXEQKJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to new and existing indolo[2,1-b]quinazoline-6,12-dione derivatives which are useful in killing malaria parasites, antimalarial compositions containing the compounds, and to methods of treating malaria with the compounds and compositions, alone or in combination with other antimalarial agents both in vitro and in vivo.
- Indolo[2,1-b]quinazoline-6,12-dione is a compound with a long history [see C. W. Bird, Tetrahedron, 19, 901 (1963), and references therein].
- the structure of the compound has been verified by x-ray crystallography: M. Brufani, et al., Experientia, 27, 1249 (1971); W. Fedeli, et al., J. Chem. Soc. Perkin Transactions 2, 621 (1974).
- Friedlander and Reschdestwensky [Ber., 48, 1843 (1915). Numerous synthetic approaches to the parent compound have been described: H. Karpf, et al., Tet Let, 3007 (1978); L. A.
- Antibacterial activity is also claimed against Staphylococcus aureus, Klebsiella pneumoniae, Mycobacterium smegmatis, and the fungi, Candida albicans [Mitscher, et al., “Antimicrobial Agents from Higher Plants. New Synthesis and Bioactivity of Tryptanthrin (Indolo[2,1-b]quinazoline-6,12-dione) and its Analogues”, Heterocycles 15, 1017-1021 (1981); Honda, G. and Tabata., M., “Isolation of Antifungal Principal Tryptanthrin from Strobilanthes Cusia O. Kuntze,”, Planta Medica, J Med.
- the first antimalarial drugs stemmed from natural remedies.
- the quinchona alkaloids were utilized for centuries before their active principals, alkaloids such as quinine and quinidine, were isolated and shown to be effective in themselves against malaria. These compounds are devoid of useful clinical antibacterial activity.
- the discovery of the first synthetic antimalarial drugs was prompted by the selective staining of plasmodium tissues by vital stains. This lead, based upon the organic chemistry of synthetic dyes, led after a period of perhaps twenty years, to the discovery of two classes of quinoline antimalarial drugs, the 4-aminoquinolines (such as chloroquine) and the 8-aminoquinolines (such as primaquine).
- the biochemical basis of the antimalarial action of these agents despite investigations spanning the last 50 years, is still unknown. Notwithstanding their extensive use as antimalarial agents, these compounds have found no clinical utility against bacterial species.
- antibacterial agents have found application in the therapy and prevention of malaria. These include compounds whose mechanisms of antibacterial action are well documented. Those interfering with folate metabolism are the best known. These include the drug combination pyrimethamine-sulfadoxine, and dapsone.
- antimalarials which inhibit the metabolism of folate within the plasmodium, such as proguanil and cycloguanil, have not found application as antibacterial agents despite their extensive clinical application as antimalarial drugs.
- Doxycycline is used for malaria prophylaxis, and recently azithromycin C has shown antimalarial activity.
- Many extremely powerful antibacterial agents such as the penicillins and cephalosporins, are devoid of antimalarial activity.
- Bacteria are prokaryotes and plasmodia are eukaryotes.
- the search for acceptable antimalarial drugs is more difficult than the search for antibacterials as the metabolic processes of the plasmodia more closely resemble those of their eukaryotic hosts while the genetic and metabolic gap between bacterial and mammals is large as they belong to different kingdoms.
- an agent that is useful for treating a bacterial infection is not necessarily useful for treating a parasitic infection like malaria.
- Indolo[2,1-b]quinazoline-6,12-dione, and substituted derivatives exhibit potent in vitro antimalarial activity against Plasmodium falciparum.
- Highly active compounds show IC 50 values (50% inhibitory concentration) in the 0.43 to 10 ng/mL concentration range, about one one-thousandth of the concentrations necessary to inhibit bacteria.
- these compounds are also highly active against strains of Plasmodium falciparum which are up to 5000-fold resistant to atovoquone, 50-fold resistant to chloroquine, and 20-fold resistant to mefloquine.
- this invention provides methods for inhibiting the growth of malaria parasites in vitro and provides methods for the prevention and treatment of malaria in vivo using indolo[2,1-b]quinazoline-6,12-dione compounds of formula I.
- A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon;
- R 1 through R 8 are independently selected from the group consisting of, but not limited to, the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH 3 or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperaziny
- prodrug containing a labile carbon-nitrogen double bond side chain exocyclic to the tryptanthin structure is shown in Formula II.
- Such an example may be more water soluble, but can be readily converted to the tryptantrin structure through hydrolysis of the carbon-nitrogen bond to give tryptanthrin.
- prodrugs are not intended to limit the invention in any way.
- Other side chains are contemplated that would make the indolo[2,1-b]quinazoline-6,12-dione compound of the above formula I a prodrug as the term is understood by one of ordinary skill in the art of medicinal chemistry.
- Prodrugs are described in Medicimal Chemestry Principles and Practice, Frank D. Cane, Royal Society of Chemistry, Cambridge England, Chapter 14, pp 215-218 (1994), which is herein incorporated by reference.
- an antimalarial compound, composition and methods are provided for treating or control of strains of Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax, either in vitro or in vivo by administering the compound or composition of the present invention.
- the present invention provides a method of inhibiting the growth of strains of P. falciparum, Plasmodium ovale, Plasmodium malariae and P. vivax in vitro comprising contacting the strains of P. falciparum, Plasmodium ovale, Plasmodium malariae and P. vivax with a growth inhibitory amount of a indolo[2,1-b]quinazoline-6,12-dione compound of the formula I.
- the invention provides methods for inhibiting the growth of malaria parasites in vitro and provides methods for the prevention and treatment of malaria in vivo using indolo[2,1-b]quinazoline-6,12-dione compounds of formula I.
- A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon;
- R 1 through R 8 are independently selected from the group consisting of the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH 3 or COOCH 2 CH 3 ), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof;
- X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prod
- the present invention proposes methods of treating human or animal subjects suffering from a malarial infection, e.g., whether of sensitive-strain or multi-drug resistant strain (MDR-malaria) origin.
- a malarial infection e.g., whether of sensitive-strain or multi-drug resistant strain (MDR-malaria) origin.
- the present invention provides a method of treating a human or animal subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a indolo[2,1-b]quinazoline-6,12-dione compound of formula (I), above, either alone or in combination with other antimalarial agents or adjuvants.
- antimalarial agents that can be used in combination with the compounds of the present invention include mefloquine, halofantrine, artesunate, artemether, chloroquine halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycin, proguanil, cycloguanil, dapsone, artemsinin, atovoquone and the like to name a few.
- These compounds can be combined with the compounds of the present invention in the same dosage, in a tablet, injectable liquid, or any other known form of administering drugs. These compounds can also be administered to a patient in a separate dosage.
- acylamino means an acyl (CO—) radical to which an amino group is appended.
- loweralkyl refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
- alkoxy refers to RO wherein R is loweralkyl as defined above.
- Representative examples of lower alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
- alkenyl refers to a branched or straight chain groups comprising two to twenty carbon atoms which also comprises one or more carbon-carbon double bonds.
- Representative alkenyl groups include 2-propenyl (i.e., ally]), 3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl, 4,8-dimethyl-3,7-nonadienyl, 3,7,11-trimethyl-2,6,10-dodecatrienyl and the like.
- alkynyl refers to a branched or straight chain comprising two to twenty carbon atoms which also comprises one or more carbon-carbon triple bonds.
- Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
- aryl refers to a phenyl or a C9- or C10-bicyclic carbocyclic ring system having one or more aromatic rings, including naphthyl, tetrahydronaphthyl indanyi, indenyl and the like.
- Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy and halo.
- arylalkyl refers to a lower alkyl radical to which is appended an aryl group.
- Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.
- arylalkylaryl refers to an arylalkyl group as previously defined appended to an aryl group.
- Representative arylalkylaryl groups include 4-benzylphenyl, 3-benzylphenyl, 4-phenethylphenyl and the like.
- arylaryl refers to an aryl group as previously defined which is appended to an aryl group.
- Representative arylaryl groups include biphenyl, 4(1-naphthyl)phenyl, 4-(2-naphthyl)phenyl and the like.
- aryloxy refers to RO wherein R is an aryl group.
- Representative arylalkoxy groups include benzyloxy, phenylethoxy and the like.
- arylalkoxy refers to a lower alkoxy radical to which is appended an aryl group.
- Representative arylalkoxy group include benzyloxy, phenylethoxy and the like.
- aryloxyaryl refers to an aryl radical to which is appended an aryloxy group.
- Representative aryloxyaryl groups include 4-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxy-1-naphthyl, 3-phenoxy-1-naphthyl and the like.
- aryloxyarylalkyl refers to an arylalkyl radical to which is appended an aryloxy group.
- Representative aryloxyarylalkyl groups include 4-phenoxyphenylmethyl, 3-phenoxyphenylmethyl, 4phenoxyphenylethyl, 3-phenoxyphenylethyl and the like.
- arylalkoxyaryl refers to an aryl radical to which is appended an arylalkoxy group.
- Representative arylalkoxyaryl groups include 4-benzyloxylphenyl, 3-benzyloxyphenyl and the like.
- arylalkoxyarylalkyl refers to an arylalkyl radical to which is appended an arylalkoxy group.
- Representative arylalkoxyarylalkyl groups include 4-benzyloxylbenzyl, 3-benzyloxybenzyl and the like.
- cycloalkyl refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- cycloalkylalkyl refers to a loweralkyl radical to which is appended a cycloalkyl group.
- Representative examples of cycloalkylalkyl include cyclopropylmethyl, cyclohexylmethyl, 2-(cyclopropyl)ethyl and the like.
- halogen or “halo” as used herein refers to iodo, bromo, chloro or fluoro and the like.
- haloalkyl refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
- heterocycle refers to an aromatic ring system composed of 5 or 6 atoms selected from the heteroatoms nitrogen, oxygen, and sulfur.
- the heterocycle may be composed of one or more heteroatoms that are either directly connected such as pyrazole or connected through carbon such as pyrimidine.
- Heterocycles can be substituted or unsubstituted with one, two or three substituents independently selected from amino, alkylamino, halogen, alkyl acylamino, lower alkylaryl, alkoxy.
- substituted heterocycle or “heterocyclic group” or heterocycle as used herein refers to any 3- or 2,5 4-membered ring containing a heteroatom selected from nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur, wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atom maybe optionally oxidized; wherein the nitrogen and sulfur heteroatoms maybe optionally quarternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring independently defined above. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred.
- the compounds of the invention comprise asymmetrically substituted carbon atoms.
- Such asymmetrically substituted carbon atoms can result in the compounds of the invention comprising mixtures of stereoisomers at a particular asymmetrically substituted carbon atom or a single stereoisomer.
- racemic mixtures, mixtures of diastereomers, as well as single diastereomers or single enantiomers of the compounds of the invention are included in the present invention. Examples thereof are shown in Table 1, Example No. 34, 35, 74, 73 and 85.
- the terms “S” and “R” configuration, as used herein, are as defined by the IUPAC 1974 Recommendations for.Section E, Fundamental Stereochemistry, Pure Appl Chem. (1976) 45, 13-30.
- ⁇ and ⁇ are employed for ring positions of cyclic compounds.
- the ⁇ -side of the reference plane is that side on which the preferred substituent lies at the lowered numbered position.
- Those substituents lying on the opposite side of the reference plane are assigned ⁇ descriptor. It should be noted that this usage differs from that for cyclic stereoparents, in which “ ⁇ ” means “below the plane” and denotes absolute configuration.
- ⁇ and ⁇ configuration are as defined by the Chemical Abstracts Index Guide - Appendix IV (1987) paragraph 203.
- compositions which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
- the in vitro assays were conducted by using a modification of the semiautomated microdilution technique of Desjardins et al. 11 and Chulay et al. 12 Two strains of Plasmodium falciparum clones, from CDC Indochina III (W-2), CDC Sierra Leone I (D-6).
- W-2 CDC Indochina III
- D-6 CDC Sierra Leone I
- the W-2 clone is susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, and quinine.
- the D-6 clone is resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine, and quinine. They were derived by direct visualization and micromanipulation from patient isolates.
- Test compounds were initially dissolved in DMSO and diluted 400-fold in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO 3 , and 10% Albumax I® (GIBCO BRL, Grand Island, N.Y.). These solutions were subsequently serially diluted 2-fold with a Biomek 1000® (Beckman, Fullerton, Calif.) over 11 different concentrations. The parasites were exposed to serial dilutions of each compound for 48 h and incubated at 37° C. with 5% O 2 , 5% CO 2 , and 90% N 2 prior to the addition of [ 3 H]hypoxanthine.
- test compounds initially dissolved in DMSO and diluted 400-fold in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO 3 , and with blood serum replacing the 10% Albumax I® (see Table 1, figures without parentheses).
- the values without parentheses indicate culture in blood serum which more closely resemble conditions in a living animal.
- MW refers to molecular weight
- W2 refers to a malaria parasite which is susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine and quinine
- D6 refers to a malaria parasite which is naturally resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine and quinine.
- the numbers associated with both W2 and D6 refer to IC 50 values and the units are ng/ml.
- the compounds 1-91 of the present are effective in treating/reducing malaria parasites. It can be seen that the lower the IC 50 concentration, the more effective the compound. The most effective compounds tested were compounds 21, 63, and 78.
- the compounds of the invention are useful in the study of the treatment of malaria in vitro.
- the in vivo efficacy of the compounds of the present invention alone or in combination with an adjuvant can be determined in a modified Thompson test. This test measures the survivability of mice and parasitemia clearance following administration of the compound or composition of the invention on days 3-5 post infection.
- 5 ⁇ 10 5 malaria parasites of one or more of the four described strains are inoculated intraperitoneally to female mice that weight approximately 24-30 g. Each compound is dissolved in 5% sodium bicarbonate, and is administered p.o. twice daily from day 3 to day 5 postinfection. Total dosage of the compounds of the invention is 0.001 to 1000 mg/kg.
- the percent suppression of parasitemia in the treated mice compared to untreated controls is determined for each test compound. Survival of mice to day 60 postinfection is considered a cure. Compounds are considered active when the survival time of the treated mice is greater than twice the control mice.
- the amount of adjuvant given is0.001 to 1000 mg/kg body weight.
- the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
- These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, bydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate,
- the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
- loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
- dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
- long chain halides such
- acids which may be employed to form pharmaceutically acceptable acid addition salts of the compounds of Formula I include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
- Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine.
- Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
- the compounds of the invention are useful in vitro in inhibiting the growth of malaria parasite, and in vivo in human and animal hosts for treating malarial parasitic infections.
- the compounds may be used alone or in compositions together with a pharmaceutically acceptable carrier.
- Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 50 mg/kg body weight daily.
- Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
- the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
- sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
- the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium Stuart.
- the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
- Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- the compounds of the present invention can also be administered in the form of liposomes.
- liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monoamellar or multiamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
- the present compositions in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like which are well known in the art of formulation of drugs.
- the preferred lipids are the phospholipids and phosphatidyl cholines (lecitins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W. (1976), p. 33 et seq.
- While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of malarial parasitic infections.
- Representative agents useful in combination with the compounds of the invention for the treatment of malaria include, for example, quinine, mefloquine, chloroquine, halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycin, proguanil, cycloguanil, dapsone, artemsinin, artesunate, artemether, atovoquone and the like.
- the above compounds to be employed in combination with the indolo[2,1-b]quinazoline-6,12-dione compounds of the invention will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 51st Edition (1997), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art such as from 0.001 to 1000 mg/kg body weight daily.
- the compounds of the invention and the other antiinfective agent can be administered together at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
- the combination can be administered as separate compositions or as a single dosage form containing both agents.
- the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R1 through R8 are independently selected from the group consisting of, but not limited to H, the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH3 or COOCH2CH3), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof, and wherein X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as the term is understood by one of ordinary skill in the art of medicinal chemistry. In other words, a side chain having a structure where a carbon-nitrogen double bond bears substituents that make the prodrug more water soluble and bioavailable.
Description
- The present invention relates to new and existing indolo[2,1-b]quinazoline-6,12-dione derivatives which are useful in killing malaria parasites, antimalarial compositions containing the compounds, and to methods of treating malaria with the compounds and compositions, alone or in combination with other antimalarial agents both in vitro and in vivo.
- The current global situation in respect to malaria has recently been detailed by Peters [W. Peters, “Drug Resistance in Malaria Parasites of Animals and Man”, Advances in Parasitology, vol. 41, pp 1-62 (1998)]. Currently, about two billion people are exposed to malaria and 400 million are infected with the disease. Between 100-200 million new cases occur each year. There are approximately 1-2 million deaths annually due to malaria. The global situation is worsening. The pertinent facts are these: very few new antimalarial drugs have been introduced in the past quarter century; there is massive pressure for the development of drug resistance due to the presence of large numbers of non-immune people in areas where malaria is efficiently transmitted; and resistance by Plasmodium falciparum and Plasmodium vivax to chloroquine is being documented in an increasingly wide geographic area.
- Other frontline drugs currently used for the treatment and prevention of malaria such as mefloquine and halofantrine, are becoming increasingly ineffective. Newly introduced artemsinin analogs (artesunate and artemether), while effective for the treatment of malaria, may be too toxic for long term administration required for prophylaxis. As a result, the idea of malaria eradication has been abandoned and replaced with the more realistic target of malaria control.
- Indolo[2,1-b]quinazoline-6,12-dione is a compound with a long history [see C. W. Bird, Tetrahedron, 19, 901 (1963), and references therein]. The structure of the compound has been verified by x-ray crystallography: M. Brufani, et al., Experientia, 27, 1249 (1971); W. Fedeli, et al., J. Chem. Soc. Perkin Transactions 2, 621 (1974). Early developments were described by Friedlander and Reschdestwensky [Ber., 48, 1843 (1915). Numerous synthetic approaches to the parent compound have been described: H. Karpf, et al., Tet Let, 3007 (1978); L. A. Mitscher, et al., Heterocycles, 15, 1017 (1981); L. Capuano, et al., Chem. Ber., 116, 741 (1983); S. Euguchi, et al., 33, 153 (1992). Indolo[2,1-b]quinazoline-6,12-dione is also a naturally occurring compound, that is found in the higher plants such as Couroupita guianensis Aubl [Bergman, et al., Tet Let., 2625 (1977)]; Strobilanthes cusia [G. Honda, et al., Planta Medica, 37, 172, (1979)]; Polygonum tinctorum and Isatis tinctorum [G. Honda, et al., Planta Medica, 38, 275 (1980). It is produced by Candida liplytica when grown in media containing an excess of tryptophan, hence its name, tryptanthrin. Indolo[2,1-b]quinzoline-6,12-dione has been shown to possess antibacterial activity against a variety of pathogenic bacteria, particularly the causative agent of tuberculosis, Mycobacterium tuberculosis. Antibacterial activity is also claimed against Staphylococcus aureus, Klebsiella pneumoniae, Mycobacterium smegmatis, and the fungi, Candida albicans [Mitscher, et al., “Antimicrobial Agents from Higher Plants. New Synthesis and Bioactivity of Tryptanthrin (Indolo[2,1-b]quinazoline-6,12-dione) and its Analogues”, Heterocycles 15, 1017-1021 (1981); Honda, G. and Tabata., M., “Isolation of Antifungal Principal Tryptanthrin from Strobilanthes Cusia O. Kuntze,”, Planta Medica, J Med. Plant Res., 36, 85-86 (1979); Mitscher, et al., “Part 1. Antitubercular Agents from Higher Plants: Synthesis and In Vitro Activity of Indolo[2,1-b]quinazoline-6,12-diones and Related Analogs”, Abstracts of Papers, 35 International Congress of Antimicrobial Agents and Chemotherapy, Abstract F16, San Diego, Calif., 1995; Baker, W. “Part II. Antitubercular Agents from Higher Plants: Antimycobacterial Activity of Azaindoloquinazolines. Novel Agents against Sensitive and Multi-drug Resistant Tuberculosis”, Abstracts of Papers, 35 International Congress of Antimicrobial Agents and Chemotherapy, Abstract F17, San Diego, Calif., 1995. To date, however, there has been no evidence or indication that Indolo[2,1-b]quinazoline-6,12-dione and derivatives exhibit anti-malarial activity against malaria parasites or would be useful in treating malaria in vivo or in vitro.
- Historically, the first antimalarial drugs stemmed from natural remedies. The quinchona alkaloids were utilized for centuries before their active principals, alkaloids such as quinine and quinidine, were isolated and shown to be effective in themselves against malaria. These compounds are devoid of useful clinical antibacterial activity. The discovery of the first synthetic antimalarial drugs was prompted by the selective staining of plasmodium tissues by vital stains. This lead, based upon the organic chemistry of synthetic dyes, led after a period of perhaps twenty years, to the discovery of two classes of quinoline antimalarial drugs, the 4-aminoquinolines (such as chloroquine) and the 8-aminoquinolines (such as primaquine). The biochemical basis of the antimalarial action of these agents, despite investigations spanning the last 50 years, is still unknown. Notwithstanding their extensive use as antimalarial agents, these compounds have found no clinical utility against bacterial species.
- Some antibacterial agents have found application in the therapy and prevention of malaria. These include compounds whose mechanisms of antibacterial action are well documented. Those interfering with folate metabolism are the best known. These include the drug combination pyrimethamine-sulfadoxine, and dapsone. However, well known antimalarials which inhibit the metabolism of folate within the plasmodium, such as proguanil and cycloguanil, have not found application as antibacterial agents despite their extensive clinical application as antimalarial drugs. Doxycycline is used for malaria prophylaxis, and recently azithromycin C has shown antimalarial activity. Many extremely powerful antibacterial agents, such as the penicillins and cephalosporins, are devoid of antimalarial activity.
- U.S. Pat. No. 5,441,955, the disclosure of which is expressly incorporated herein by reference, describes the general Formula I described herein, with the exception that it does not disclose that X can be a side chain necessary to make the compound of Formula I a prodrug. However, the '955 patent focuses on antibacterial compounds for treating bacterial infections, but fails to contemplate treating malaria parasites with these compounds or using them as antimalarial agents. Thus, the inventors of this invention have discovered the unexpected result of these particular compounds, and the compounds with side chains rendering the compounds prodrugs, as antimalarial agents.
- That there is little relationship between antibacterial activity in a drug such as described in the '955 patent and antimalarial activity in a drug is not surprising. The bacteria and the plasmodia are very distant genetically: Bacteria are prokaryotes and plasmodia are eukaryotes. Thus, the search for acceptable antimalarial drugs is more difficult than the search for antibacterials as the metabolic processes of the plasmodia more closely resemble those of their eukaryotic hosts while the genetic and metabolic gap between bacterial and mammals is large as they belong to different kingdoms. Hence, an agent that is useful for treating a bacterial infection is not necessarily useful for treating a parasitic infection like malaria.
- The inventors of the present invention have surprisingly -discovered that Indolo[2,1-b]quinazoline-6,12-dione, and substituted derivatives, exhibit potent in vitro antimalarial activity against Plasmodium falciparum. Highly active compounds show IC50 values (50% inhibitory concentration) in the 0.43 to 10 ng/mL concentration range, about one one-thousandth of the concentrations necessary to inhibit bacteria. Furthermore, these compounds are also highly active against strains of Plasmodium falciparum which are up to 5000-fold resistant to atovoquone, 50-fold resistant to chloroquine, and 20-fold resistant to mefloquine. Therefore, this invention provides methods for inhibiting the growth of malaria parasites in vitro and provides methods for the prevention and treatment of malaria in vivo using indolo[2,1-b]quinazoline-6,12-dione compounds of formula I.
wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R1 through R8 are independently selected from the group consisting of, but not limited to, the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH3 or COOCH2CH3), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof; and wherein X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as the term is understood by one of ordinary skill in the art of medicinal chemistry. In other words, a side chain having a structure where a carbon-nitrogen double bond bears substituents that make the prodrug more water soluble and bioavailable. Improved-bioavailability results in a lower effective dosage. It also makes more predictable and uniform absorbance which increases the predictability of the response which in turn increases safety by reducing drug side effects. - An example of a prodrug containing a labile carbon-nitrogen double bond side chain exocyclic to the tryptanthin structure is shown in Formula II. Such an example may be more water soluble, but can be readily converted to the tryptantrin structure through hydrolysis of the carbon-nitrogen bond to give tryptanthrin.
-
- These examples of prodrugs are not intended to limit the invention in any way. Other side chains are contemplated that would make the indolo[2,1-b]quinazoline-6,12-dione compound of the above formula I a prodrug as the term is understood by one of ordinary skill in the art of medicinal chemistry. Prodrugs are described in Medicimal Chemestry Principles and Practice, Frank D. Cane, Royal Society of Chemistry, Cambridge England, Chapter 14, pp 215-218 (1994), which is herein incorporated by reference.
- In accordance with the present invention, an antimalarial compound, composition and methods are provided for treating or control of strains of Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax, either in vitro or in vivo by administering the compound or composition of the present invention. Thus, one aspect the present invention provides a method of inhibiting the growth of strains of P. falciparum, Plasmodium ovale, Plasmodium malariae and P. vivax in vitro comprising contacting the strains of P. falciparum, Plasmodium ovale, Plasmodium malariae and P. vivax with a growth inhibitory amount of a indolo[2,1-b]quinazoline-6,12-dione compound of the formula I.
-
- wherein A, B, C, D, E, F, G and H are independently selected from carbon and nitrogen, or A and B or C and D can be taken together to be nitrogen or sulfur, with the proviso that not more than three of A, B, C, D, E, F, G and H are other than carbon; wherein R1 through R8 are independently selected from the group consisting of the halogens (F, Cl, Br, and I), alkyl groups, trifluoromethyl groups, methoxyl groups, the carboxy methyl or carboxy ethyl group (COOCH3 or COOCH2CH3), nitro, aryl, heteroaryl, cyano, amino, dialkylaminoalkyl, 1-(4-alkylpiperazinyl), and the pharmaceutically acceptable salts thereof; further wherein X is independently selected from the group consisting of any atom especially oxygen, or any side chain necessary to make the indolo[2,1-b]quinazoline-6,12-dione compound a “prodrug” as described above and as the term is understood by one of ordinary skill in the art of medicinal chemistry.
- In another aspect, the present invention proposes methods of treating human or animal subjects suffering from a malarial infection, e.g., whether of sensitive-strain or multi-drug resistant strain (MDR-malaria) origin. Thus, the present invention provides a method of treating a human or animal subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a indolo[2,1-b]quinazoline-6,12-dione compound of formula (I), above, either alone or in combination with other antimalarial agents or adjuvants.
- Other antimalarial agents that can be used in combination with the compounds of the present invention include mefloquine, halofantrine, artesunate, artemether, chloroquine halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycin, proguanil, cycloguanil, dapsone, artemsinin, atovoquone and the like to name a few. These compounds can be combined with the compounds of the present invention in the same dosage, in a tablet, injectable liquid, or any other known form of administering drugs. These compounds can also be administered to a patient in a separate dosage.
- Other adjuvants that can be used in combination with the compounds of the present invention are any other antiparasitic drugs.
- The term “acylamino” means an acyl (CO—) radical to which an amino group is appended.
- The term “loweralkyl” as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.
- The term “alkoxy” as used herein refers to RO wherein R is loweralkyl as defined above. Representative examples of lower alkoxy groups include methoxy, ethoxy, t-butoxy and the like.
- The term “alkenyl” as used herein refers to a branched or straight chain groups comprising two to twenty carbon atoms which also comprises one or more carbon-carbon double bonds. Representative alkenyl groups include 2-propenyl (i.e., ally]), 3-methyl-2-butenyl, 3,7-dimethyl-2,6-octadienyl, 4,8-dimethyl-3,7-nonadienyl, 3,7,11-trimethyl-2,6,10-dodecatrienyl and the like.
- The term “alkynyl” as used herein refers to a branched or straight chain comprising two to twenty carbon atoms which also comprises one or more carbon-carbon triple bonds. Representative alkynyl groups include ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
- The term “aryl” as used herein refers to a phenyl or a C9- or C10-bicyclic carbocyclic ring system having one or more aromatic rings, including naphthyl, tetrahydronaphthyl indanyi, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy and halo.
- The term “arylalkyl” as used herein refers to a lower alkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.
- The term “arylalkylaryl” as used herein refers to an arylalkyl group as previously defined appended to an aryl group. Representative arylalkylaryl groups include 4-benzylphenyl, 3-benzylphenyl, 4-phenethylphenyl and the like.
- The term “arylaryl” as used herein refers to an aryl group as previously defined which is appended to an aryl group. Representative arylaryl groups include biphenyl, 4(1-naphthyl)phenyl, 4-(2-naphthyl)phenyl and the like.
- The term “aryloxy” as used herein refers to RO wherein R is an aryl group. Representative arylalkoxy groups include benzyloxy, phenylethoxy and the like.
- The term “arylalkoxy” as used herein refers to a lower alkoxy radical to which is appended an aryl group. Representative arylalkoxy group include benzyloxy, phenylethoxy and the like.
- The term “aryloxyaryl” as used herein refers to an aryl radical to which is appended an aryloxy group. Representative aryloxyaryl groups include 4-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxy-1-naphthyl, 3-phenoxy-1-naphthyl and the like.
- The term “aryloxyarylalkyl” as used herein refers to an arylalkyl radical to which is appended an aryloxy group. Representative aryloxyarylalkyl groups include 4-phenoxyphenylmethyl, 3-phenoxyphenylmethyl, 4phenoxyphenylethyl, 3-phenoxyphenylethyl and the like.
- The term “arylalkoxyaryl” as used herein refers to an aryl radical to which is appended an arylalkoxy group. Representative arylalkoxyaryl groups include 4-benzyloxylphenyl, 3-benzyloxyphenyl and the like.
- The term “arylalkoxyarylalkyl” as used herein refers to an arylalkyl radical to which is appended an arylalkoxy group. Representative arylalkoxyarylalkyl groups include 4-benzyloxylbenzyl, 3-benzyloxybenzyl and the like.
- The term “cycloalkyl” as used herein refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
- The term “cycloalkylalkyl” as used herein refers to a loweralkyl radical to which is appended a cycloalkyl group. Representative examples of cycloalkylalkyl include cyclopropylmethyl, cyclohexylmethyl, 2-(cyclopropyl)ethyl and the like.
- The term “halogen” or “halo” as used herein refers to iodo, bromo, chloro or fluoro and the like.
- The term “haloalkyl” as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.
- The term “heterocycle” as used herein refers to an aromatic ring system composed of 5 or 6 atoms selected from the heteroatoms nitrogen, oxygen, and sulfur. The heterocycle may be composed of one or more heteroatoms that are either directly connected such as pyrazole or connected through carbon such as pyrimidine. Heterocycles can be substituted or unsubstituted with one, two or three substituents independently selected from amino, alkylamino, halogen, alkyl acylamino, lower alkylaryl, alkoxy.
- The term “substituted heterocycle” or “heterocyclic group” or heterocycle as used herein refers to any 3- or 2,5 4-membered ring containing a heteroatom selected from nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur, wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur atom maybe optionally oxidized; wherein the nitrogen and sulfur heteroatoms maybe optionally quarternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another 5- or 6-membered heterocyclic ring independently defined above. Heterocyclics in which nitrogen is the heteroatom are preferred. Fully saturated heterocyclics are also preferred.
- The compounds of the invention comprise asymmetrically substituted carbon atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the invention comprising mixtures of stereoisomers at a particular asymmetrically substituted carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of diastereomers, as well as single diastereomers or single enantiomers of the compounds of the invention are included in the present invention. Examples thereof are shown in Table 1, Example No. 34, 35, 74, 73 and 85. The terms “S” and “R” configuration, as used herein, are as defined by the IUPAC 1974 Recommendations for.Section E, Fundamental Stereochemistry, Pure Appl Chem. (1976) 45, 13-30. The terms α and β are employed for ring positions of cyclic compounds. The α-side of the reference plane is that side on which the preferred substituent lies at the lowered numbered position. Those substituents lying on the opposite side of the reference plane are assigned β descriptor. It should be noted that this usage differs from that for cyclic stereoparents, in which “α” means “below the plane” and denotes absolute configuration. The terms α and β configuration, as used herein, are as defined by the Chemical Abstracts Index Guide-Appendix IV (1987) paragraph 203.
- In yet a further aspect of the present invention, pharmaceutical compositions are provided which comprise a compound of the present invention in combination with a pharmaceutically acceptable carrier.
- The in vitro assays were conducted by using a modification of the semiautomated microdilution technique of Desjardins et al.11 and Chulay et al.12 Two strains of Plasmodium falciparum clones, from CDC Indochina III (W-2), CDC Sierra Leone I (D-6). The W-2 clone is susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine, and quinine. The D-6 clone is resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine, and quinine. They were derived by direct visualization and micromanipulation from patient isolates.13 Test compounds were initially dissolved in DMSO and diluted 400-fold in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO3, and 10% Albumax I® (GIBCO BRL, Grand Island, N.Y.). These solutions were subsequently serially diluted 2-fold with a Biomek 1000® (Beckman, Fullerton, Calif.) over 11 different concentrations. The parasites were exposed to serial dilutions of each compound for 48 h and incubated at 37° C. with 5% O2, 5% CO2, and 90% N2 prior to the addition of [3H]hypoxanthine. After a further incubation of 18 h, parasite DNA was harvested from each microtiter well using Packard Filtermate 196 Harvester® (Meriden, Conn.) onto glass filters. Uptake of [3H]hypoxanthine was measured with a Packard Topcount scintillation counter. Concentration-response data were analyzed by a nonlinear regression logistic dose-response model, and the IC50 values (50% inhibitory concentrations) for each compound were calculated (see Table 1, values within parentheses ( )). This procedure was repeated with the test compounds initially dissolved in DMSO and diluted 400-fold in RPMI 1640 culture medium supplemented with 25 mM Hepes, 32 mM HaHCO3, and with blood serum replacing the 10% Albumax I® (see Table 1, figures without parentheses). The values without parentheses indicate culture in blood serum which more closely resemble conditions in a living animal.
- Four strains of Plasmodium falciparum clones, from CDC Indochina III (W-2), CDC Sierra Leone I (D-6), Thai WR75-TM9, and Thai TM90C2B were utilized in susceptibility testing and the IC50 results appear in Table 1.
TABLE 1 In Vitro Antimalarial Activity. Concentration of Indolo[2,3-b]quinazoline-6,12-dione Inhibiting uptake of [3H]Hypoxanthine by Parasitized Red Blood Cells by 50% (IC50, ng/mL) Example IC50 IC50 IC50 IC50 No. Structure (W-2) (D-6) (TM90C2B) (WR75-TM9) 1. (69)* (69) 2. (15626) (12481) 3. (>50000) (>50000) 4 (2.33) 15.335* (4.07) 18.888 29.846 27.319 7.165 5. (263.86) (313.106) 6. (502.79) (527) 7. (512.7) (576.53) 8. (62) (62) 9. (403) (471) 10. (131) (138) 11. (2.8) 14.678 (4.9) 22.068 16.383 35.991 1.587 12. (1.6) 5.274 5.787 6.539 (4.9) 8.535 14.239 11.005 9.738 16.914 11.113 11.951 16.249 19.374 13. (5.1) 4.335 (14.3) 14.842 10.531 9.837 21.542 13. (5.8) 10.091 (10.0) 23.258 20.119 10.499 14. (5.76) (10.17) 15. (81.99) (125.58) 16. (1014) (2160) 17. (0.84) 2.125 (1.53) 4.928 4.207 9.932 8.002 18. (512.93) (812.73) 19. (1.58) 8.138 (2.57) 13.523 9.784 18.937 .485 20. (734.34) (1054.46) 21. (0.43) 1.278 (0.93) 0.926 2.302 2.997 1.349 22. (262.92) (277.72) 23. (1.67) (3.97) 24. (0.91) 0.912 4.638 (2.01) 10.078 7.782 17.411 8.059 25. (1990.37) (1842.69) 26. (609.29) (589.01) 27. (1.79) 35.649 (3.01) 95.331 41.090 139.605 5.86 28. (126) (19.925) (124) (38.541) 29. (130.58) (149.32) 30. (354.29) (499.81) 32. (2588.82) (3848.62) 33. (79.58) (67.06) 34. (601.05) (588.27) 35. (133.86) (103.44) 36. (4815.61) (4204.57) 37. (3483.15) (3778.15) 38. (203.16) (241.86) 39. (1.88) 1.870 (3.57) 3.570 46.039 4.203 40. No entry 41. (7.66) (12.34) 42. (63.17) (76.43) 43. (23,000) (38,236) 44. (5859.64) (6924.46) 45. (0.728) 4.741 (1.28) 6.767 8.759 1.147 14.152 46 (6.32) 22.994 (7.61) 42.6 24.417 66.441 47. No Entry 48. (7.74) 58.100 (13.9 97.106 55.796 66.666 157.162 48. (508.19) (584.37) 49. (74.75) (73.93) 50. (11.16 (44.22) 51. (8760) (8693) 52. (64.69) (73.33) 53. (4872.21) (9006) 54. (124.03) (74.58) 55. (2.1) 2.303 (7.2) 11.238 5.483 14.216 56. (117) (216) 57. (10.58) 28.943 (20.33) 46.492 62.233 82.551 58. (2.73) 4.272 (4.52) 10.461 8.095 17.291 59. (2.47) 17.707 (4.37) 37.894 24.005 1.306 60. (67.86) (78.08) 61. (187) (247) 62. (16) (31.27) 63. (1.5) 1.228 (3.16) 0.946 1.162 1.965 64. (9.25) 36.831 (15.86) 70.142 38.338 38.389 65 (153.98) (258.88) 66. (448.53) (516.51) 67. (4423.91) (4435.40) 68. (3.86) 2.455 (7.86) 4.121 3.731 5.469 69. (2.13) 8.494 (4.04) 12.333 10.170 23.876 70. (8.69) 6.098 (13.22) 5.736 77.808 10.999 24.37 71. (120.06) (143.32) 72. (7465) (7860) 73. (3.75) 2.855 (5.40) 4.889 4.464 10.506 74. (3.52) 59.846 (2.19) 79.578 42.505 127.39 75. (572.94) (534.47) 76. (159.65) (223.53) 77. (165.32) (220.3) 78. (0.86) 0.935 (0.93) 1.966 1.764 3.297 79. (68.76) (69.96) 80. (6902.53) (7965.51) 81. (73.92) (110.16) 82. (124) (62.82) 83. (1.8) 7.186 (3.11) 15.141 12.864 25.717 84. (937.57) (1710.33) 85. (105.36) (135.96) 86. (2.3) 1.908 (3.6) 3.63 2.079 35.678 4.506 87. (3.51) 1.252 (4.92) 2.310 0.696 4.438 88. (177.45) (490.16) 89. (68.77) (111.69) 90. (3.93) 15.601 (7.59) 16.320 6.145 30.045 91. (1.8) 5.521 4.977 (0.24) 9.064 10.137 9.825 4.594 9.941 5.438 4.449 9.941 16.412
*Values in parenthesis represent assays conducted in Albumax.
**Values without parenthesis represent assays conducted in blood plasma.
- Regarding the foregoing compounds, MW refers to molecular weight, W2 refers to a malaria parasite which is susceptible to mefloquine but resistant to chloroquine, sulfadoxine, pyrimethamine and quinine. D6 refers to a malaria parasite which is naturally resistant to mefloquine but susceptible to chloroquine, sulfadoxine, pyrimethamine and quinine. The numbers associated with both W2 and D6 refer to IC50 values and the units are ng/ml.
- As is shown in Table 1, the compounds 1-91 of the present are effective in treating/reducing malaria parasites. It can be seen that the lower the IC50 concentration, the more effective the compound. The most effective compounds tested were compounds 21, 63, and 78.
- The compounds of the invention are useful in the study of the treatment of malaria in vitro.
- Lin, A. J.; Zikry, A. B.; Kyle, D. E. J. Med. Chem., 1997, 40 (9), 1399-1400, which disclosure is herein expressly incorporated by reference, describes in detail the procedures followed by the inventors for in vitro antimalarial studies. That disclosure also describes the procedures for conducting in vivo antimalarial studies.
- In Vivo Inhibition of Plasmodium falciparum, Plasmodium ovale, Plasmodium malariae and Plasmodium vivax.
- The in vivo efficacy of the compounds of the present invention alone or in combination with an adjuvant can be determined in a modified Thompson test. This test measures the survivability of mice and parasitemia clearance following administration of the compound or composition of the invention on days 3-5 post infection. In brief, 5×105 malaria parasites of one or more of the four described strains are inoculated intraperitoneally to female mice that weight approximately 24-30 g. Each compound is dissolved in 5% sodium bicarbonate, and is administered p.o. twice daily from day 3 to day 5 postinfection. Total dosage of the compounds of the invention is 0.001 to 1000 mg/kg. The percent suppression of parasitemia in the treated mice compared to untreated controls is determined for each test compound. Survival of mice to day 60 postinfection is considered a cure. Compounds are considered active when the survival time of the treated mice is greater than twice the control mice.
- When the compounds of the present invention are administered with an adjuvant, the amount of adjuvant given is0.001 to 1000 mg/kg body weight.
- The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, bydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
- Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts of the compounds of Formula I include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
- Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. The compounds of the invention are useful in vitro in inhibiting the growth of malaria parasite, and in vivo in human and animal hosts for treating malarial parasitic infections. The compounds may be used alone or in compositions together with a pharmaceutically acceptable carrier.
- Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 50 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
- The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
- The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
- Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
- Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
- Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium Stuart. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
- Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
- The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monoamellar or multiamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like which are well known in the art of formulation of drugs. The preferred lipids are the phospholipids and phosphatidyl cholines (lecitins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.W. (1976), p. 33 et seq.
- While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more other agents used in the treatment of malarial parasitic infections. Representative agents useful in combination with the compounds of the invention for the treatment of malaria include, for example, quinine, mefloquine, chloroquine, halofantrine, primaquine, sulfadoxine, sulfalene, pyrimethamine, doxycycline, tetracycline, azithromycin, proguanil, cycloguanil, dapsone, artemsinin, artesunate, artemether, atovoquone and the like.
- The above compounds to be employed in combination with the indolo[2,1-b]quinazoline-6,12-dione compounds of the invention will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 51st Edition (1997), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art such as from 0.001 to 1000 mg/kg body weight daily. The compounds of the invention and the other antiinfective agent can be administered together at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
- While the preferred embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
- 1. U.S. Pat. No. 5,441,955 “Indolo[2,1-b]quinazoline-6,12-dione Antibacterial Compounds and Methods of Use Thereof”
- 2. Mitscher, et al., “Antimicrobial Agents from Higher Plants. New Synthesis and Bioactivity of Tryptanthrin (Indolo[2,1-b]quinzoline-6,12-dione) and its Analogoues”, Heterocycles 15, 1017-1021 (1981)
- 3. Honda, G. and Tabata., M., “Isolation of Antifungal Principal Tryptanthrin from Strobilanthes Cusia O. Kuntze,”, Planta Medica, J Med. Plant Res., 36, 85-86 (1979).
- 4. Part 1. Antitubercular Agents from Higher Plants: Synthesis and In Vitro Activity of Indolo[2,1-b]quinazoline-6,12-diones and Related Analogs, Mitscher, L, et al., Abstracts of Papers, 35 International Congress of Antimicrobial Agents and Chemotherapy, Abstract F16, San Diego, Calif., 1995.
- 5. Baker, W. “Part II. Antitubercular Agents from Higher Plants: Antimycobacterial Activity of Azaindoloquinazolines. Novel Agents against Sensitive and Multidrug Resistant Tuberculosis”, Abstracts of Papers, 35 International Congress of Antimicrobial Agents and Chemotherapy, Abstract F17, San Diego, Calif., 1995.
- 6. Bergman, J., et al., “The Structure of Some Indolic Constituents in Couroupita Guaianensis Aubl., Tetrahedron Letters, 30, 2625-2626 (1977).
- 7. Lin, A. J.; Zilry, A. B.; Kyle, D. E. J. Med. Chem., 1997,40 (9), 1399-1400.
- 11. R. E. Desjardins, C. J. Canfield, D. E. Haynes, and J. D. Chulay, Quantitative Assessment of Activity In Vitro by a Semiautomated Microdilution Technique, Antimicrob. Agents Chemother., 16, 710-718-1979).
- 12. J. D. Chulay, J. D. Haynes, and C. L. Diggs, Plasmodium falciparum: Assessment of In Vitro Growth by [3H]hypoxanthine Incorporation, Exp. Parasitol., 55, 138-146 (1983).
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/364,425 US8012987B2 (en) | 1998-09-30 | 2006-02-28 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10239998P | 1998-09-30 | 1998-09-30 | |
US09/407,196 US6284772B1 (en) | 1998-09-30 | 1999-09-28 | Indolo[2,1-B] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US09/850,996 US6531487B2 (en) | 1998-09-30 | 2001-05-08 | Indolo[2,1-b] quinazole-6, 12-dione antimalarial compounds and methods of treating malaria therewith |
US10/384,979 US20030191138A1 (en) | 1998-09-30 | 2003-03-10 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US11/364,425 US8012987B2 (en) | 1998-09-30 | 2006-02-28 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/384,979 Division US20030191138A1 (en) | 1998-09-30 | 2003-03-10 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
Publications (2)
Publication Number | Publication Date |
---|---|
US20060160827A1 true US20060160827A1 (en) | 2006-07-20 |
US8012987B2 US8012987B2 (en) | 2011-09-06 |
Family
ID=22289636
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/407,196 Expired - Fee Related US6284772B1 (en) | 1998-09-30 | 1999-09-28 | Indolo[2,1-B] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US09/850,996 Expired - Fee Related US6531487B2 (en) | 1998-09-30 | 2001-05-08 | Indolo[2,1-b] quinazole-6, 12-dione antimalarial compounds and methods of treating malaria therewith |
US10/384,979 Abandoned US20030191138A1 (en) | 1998-09-30 | 2003-03-10 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US11/364,425 Expired - Fee Related US8012987B2 (en) | 1998-09-30 | 2006-02-28 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/407,196 Expired - Fee Related US6284772B1 (en) | 1998-09-30 | 1999-09-28 | Indolo[2,1-B] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US09/850,996 Expired - Fee Related US6531487B2 (en) | 1998-09-30 | 2001-05-08 | Indolo[2,1-b] quinazole-6, 12-dione antimalarial compounds and methods of treating malaria therewith |
US10/384,979 Abandoned US20030191138A1 (en) | 1998-09-30 | 2003-03-10 | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
Country Status (8)
Country | Link |
---|---|
US (4) | US6284772B1 (en) |
EP (1) | EP1032574B1 (en) |
AP (1) | AP1393A (en) |
AU (1) | AU765401B2 (en) |
CA (1) | CA2317711A1 (en) |
DE (1) | DE69936285D1 (en) |
WO (1) | WO2000018769A2 (en) |
ZA (1) | ZA200003315B (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6284772B1 (en) * | 1998-09-30 | 2001-09-04 | The United States Of America As Represented By The Secretary Of The Army | Indolo[2,1-B] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US20040242632A1 (en) * | 2001-11-09 | 2004-12-02 | Charous B. Lauren | Method for treating inflammatory bowel disease |
WO2003069303A2 (en) * | 2002-02-09 | 2003-08-21 | U.S. Army Medical Research And Material Command | Antimalarial and antiproliferative pharmacophore models, novel tryptanthrin compounds having increased solubility, and methods of making and using thereof |
EP1594524B1 (en) * | 2003-01-21 | 2012-08-15 | Novartis Vaccines and Diagnostics, Inc. | Use of tryptanthrin compounds for immune potentiation |
US7893096B2 (en) | 2003-03-28 | 2011-02-22 | Novartis Vaccines And Diagnostics, Inc. | Use of small molecule compounds for immunopotentiation |
DE10315654A1 (en) * | 2003-04-04 | 2004-11-04 | Universitätsklinikum Charité an der Humboldt-Universität zu Berlin Technologietransferstelle | 8-nitro-tryptanthrin and other tryptanthrin derivatives for the treatment of diseases caused by highly proliferating cells |
US7256198B2 (en) | 2004-02-18 | 2007-08-14 | Wyeth | Pyrimidoindolones and methods for using same |
WO2006115509A2 (en) | 2004-06-24 | 2006-11-02 | Novartis Vaccines And Diagnostics Inc. | Small molecule immunopotentiators and assays for their detection |
EP2277595A3 (en) | 2004-06-24 | 2011-09-28 | Novartis Vaccines and Diagnostics, Inc. | Compounds for immunopotentiation |
ATE429921T1 (en) * | 2005-01-14 | 2009-05-15 | Glaxosmithkline Zagreb | 9A-CARBAMOYL AND THIOCARBAMOYLAZALIDE WITH ANTIMALARIA EFFECT |
WO2007036947A1 (en) * | 2005-09-30 | 2007-04-05 | Ipca Laboratories Limited | Delayed release anti-malarial composition |
ATE464301T1 (en) | 2005-10-04 | 2010-04-15 | Director General Defence Res & | COMPOUND ISOLATED FROM GOMPHOSTEMMA LEVEL AGAINST MALARIA |
ATE539079T1 (en) * | 2006-03-23 | 2012-01-15 | Novartis Ag | IMIDAZOCHINOXALINE COMPOUNDS AS IMMUNE MODULATORS |
EP2007765B1 (en) * | 2006-03-23 | 2012-06-27 | Novartis AG | Immunopotentiating compounds |
MX2010012261A (en) * | 2008-05-09 | 2011-04-07 | Tolmar Inc | Proguanil to treat skin/mucosal diseases. |
MX2011007897A (en) * | 2009-01-30 | 2011-09-15 | 4Sc Ag | Sulfamoyl- phenyl-ureido benzamidine-derivatives as antimalarial agents. |
CN103570726B (en) | 2013-07-15 | 2016-04-06 | 上海天慈生物谷生物工程有限公司 | N-alkyl couroupitine A derivative and its preparation method and application |
CN103570727B (en) | 2013-11-12 | 2015-08-19 | 复旦大学 | A kind of N-benzyl couroupitine A derivative and its preparation method and application |
RU2694058C1 (en) * | 2019-04-08 | 2019-07-09 | Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б. Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) | Water-soluble derivative of tryptane-trin, having anti-tumor, anti-inflammatory and antimicrobial activity, and increasing therapeutic activity of anti-tumor antibiotics |
EP4017854A1 (en) * | 2019-08-20 | 2022-06-29 | CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental | Pyrazino [1,2-b]quinazoline-3,6-diones derivatives, their production and uses thereof |
CN114057760B (en) * | 2021-11-15 | 2023-10-20 | 成都大学 | Indoloquinazolinone spiro 1, 3-dioxolane compound, preparation method and application thereof |
CN115124531A (en) * | 2022-08-09 | 2022-09-30 | 贵州大学 | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof |
CN115197227A (en) * | 2022-08-09 | 2022-10-18 | 贵州大学 | Tryptanthrin 1-position or 3-position substituted aromatic thioether derivative, and preparation method and application thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5441955A (en) * | 1993-11-19 | 1995-08-15 | Pathogenesis Corporation | Indolo[2,1-biquinazoline-6,12-dione antibacterial compounds and methods of use thereof |
US5767315A (en) * | 1994-10-18 | 1998-06-16 | Mita Industrial Co., Ltd. | Naphthylenediamine derivative |
US5817810A (en) * | 1995-07-26 | 1998-10-06 | Mita Industrial Co., Ltd. | Tryptanthrine compounds |
US6284772B1 (en) * | 1998-09-30 | 2001-09-04 | The United States Of America As Represented By The Secretary Of The Army | Indolo[2,1-B] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4114990A1 (en) * | 1991-05-08 | 1992-11-12 | Basf Ag | TRYPTANTHINE DERIVATIVES |
US5616441A (en) | 1994-09-20 | 1997-04-01 | Mita Industrial Co., Ltd. | Tryptoanthorine derivative contained in electrophotosensitive material |
EP0718298A1 (en) | 1994-11-29 | 1996-06-26 | Mita Industrial Co. Ltd. | Electron transporting tryptoanthrinime derivatives |
US5773613A (en) * | 1994-11-29 | 1998-06-30 | Mita Industrial Co., Ltd. | Tryptoanthrinimine derivative and electrophotosensitive material using the same |
JP3264618B2 (en) | 1995-07-26 | 2002-03-11 | 京セラミタ株式会社 | Electrophotographic photoreceptor |
-
1999
- 1999-09-28 US US09/407,196 patent/US6284772B1/en not_active Expired - Fee Related
- 1999-09-28 WO PCT/US1999/022569 patent/WO2000018769A2/en active IP Right Grant
- 1999-09-28 AU AU65023/99A patent/AU765401B2/en not_active Ceased
- 1999-09-28 DE DE69936285T patent/DE69936285D1/en not_active Expired - Lifetime
- 1999-09-28 AP APAP/P/2000/001855A patent/AP1393A/en active
- 1999-09-28 CA CA002317711A patent/CA2317711A1/en not_active Abandoned
- 1999-09-28 EP EP99952979A patent/EP1032574B1/en not_active Expired - Lifetime
-
2000
- 2000-06-30 ZA ZA200003315A patent/ZA200003315B/en unknown
-
2001
- 2001-05-08 US US09/850,996 patent/US6531487B2/en not_active Expired - Fee Related
-
2003
- 2003-03-10 US US10/384,979 patent/US20030191138A1/en not_active Abandoned
-
2006
- 2006-02-28 US US11/364,425 patent/US8012987B2/en not_active Expired - Fee Related
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5441955A (en) * | 1993-11-19 | 1995-08-15 | Pathogenesis Corporation | Indolo[2,1-biquinazoline-6,12-dione antibacterial compounds and methods of use thereof |
US5767315A (en) * | 1994-10-18 | 1998-06-16 | Mita Industrial Co., Ltd. | Naphthylenediamine derivative |
US5817810A (en) * | 1995-07-26 | 1998-10-06 | Mita Industrial Co., Ltd. | Tryptanthrine compounds |
US6284772B1 (en) * | 1998-09-30 | 2001-09-04 | The United States Of America As Represented By The Secretary Of The Army | Indolo[2,1-B] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith |
US6531487B2 (en) * | 1998-09-30 | 2003-03-11 | The United States Of America As Represented By The Secretary Of The Army | Indolo[2,1-b] quinazole-6, 12-dione antimalarial compounds and methods of treating malaria therewith |
Also Published As
Publication number | Publication date |
---|---|
AU765401B2 (en) | 2003-09-18 |
ZA200003315B (en) | 2001-07-11 |
US6284772B1 (en) | 2001-09-04 |
US20030191138A1 (en) | 2003-10-09 |
AP2000001855A0 (en) | 2000-06-30 |
US6531487B2 (en) | 2003-03-11 |
US20010034350A1 (en) | 2001-10-25 |
WO2000018769A3 (en) | 2000-09-08 |
EP1032574B1 (en) | 2007-06-13 |
DE69936285D1 (en) | 2007-07-26 |
EP1032574A3 (en) | 2000-12-20 |
AU6502399A (en) | 2000-04-17 |
AP1393A (en) | 2005-04-19 |
EP1032574A2 (en) | 2000-09-06 |
US8012987B2 (en) | 2011-09-06 |
WO2000018769A2 (en) | 2000-04-06 |
CA2317711A1 (en) | 2000-04-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8012987B2 (en) | Indolo[2,1-b] quinazole-6,12-dione antimalarial compounds and methods of treating malaria therewith | |
AU704955B2 (en) | Use of CGMP-phosphodiesterase inhibitors to treat impotence | |
DE69633734T2 (en) | ANTIBACTERIAL NITROIMIDAZOLE COMPOUNDS AND METHOD FOR THEIR USE | |
EP1095042B9 (en) | Antiparasitic artemisinin derivatives (endoperoxides) | |
JP2013506716A (en) | Methods for treating diseases using proanthocyanidin oligomers such as crofelemer | |
CA2388729A1 (en) | Imidazopyridine derivatives as phosphodiesterase vii inhibitors | |
US6087358A (en) | Nitro-[2,1-b]imidazopyran compounds and antibacterial uses thereof | |
KR100417506B1 (en) | 5ht1 antagonists for antidepressant therapy | |
DE60122559T2 (en) | INDOLDERIVATE AS PDE5 INHIBITORS | |
Patinote et al. | Fused Azolo-Quinoxalines: Candidates for Medicinal Chemistry. A Review of their Biological Applications | |
US3852450A (en) | Antibacterial compositions containing rifampicin and a pyrimidine derivative | |
KR100325276B1 (en) | Use of N-(pyridinyl)-1H-indol-1-amines for the preparation of a medicament for the treatment of obsessive-compulsive disorders | |
JPH10507446A (en) | Bis-2-aminopyridines, methods for their production and their use for controlling parasite infection | |
US4321267A (en) | 1-Substituted-4 (1H)-pyridinone hydrazones active against Giardia lamblia and Trichomonas vaginalis | |
US4321274A (en) | Substituted 1-(cinnamylideneamino)-3-benzyli-deneaminoguanidines active against Giardia lamblia and Trichomonas vaginalis | |
US3555085A (en) | Nitro-trifluoromethylthiobenzamides | |
BR112021011875A2 (en) | COMPOUND, PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL, COMPOUND FOR USE, AND, METHODS FOR PRODUCING A COMPOUND, TO PREVENT AND/OR TREAT A PROTOZOAN INFECTION AND TO INACTIVATE PROTOZOAN INFECTION IN A CELL | |
JPH0386823A (en) | Antidepressant | |
MXPA96005153A (en) | Pharmaceutical agents for the treatment of chronic and agu inflammatory diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: UNITED STATES ARMY,MARYLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PITZER, KEVIN K.;SCOVILL, JOHN P.;KYLE, DENNIS E.;AND OTHERS;SIGNING DATES FROM 19990903 TO 19990927;REEL/FRAME:023987/0844 Owner name: UNITED STATES ARMY, MARYLAND Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PITZER, KEVIN K.;SCOVILL, JOHN P.;KYLE, DENNIS E.;AND OTHERS;SIGNING DATES FROM 19990903 TO 19990927;REEL/FRAME:023987/0844 |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20150906 |